Of the many phenylpropylamines which show analgesic activity, the two most important are methadone and propoxyphene. The optically active alpha-dextro stereoisomer of propoxyphene is the only stereoisomer of propoxyphene which possesses analgesic properties. It is commonly prescribed in its hydrochloride salt form which is a bitter, white crystalline powder freely soluble in water and soluble in alcohol. Its chemical name is .alpha.-d-1,2diphenyl-2-propionoxy-3-methyl-4-dimethylamino butane hydrochloride and is sold under several different trademarks including for example DARVON, DOLENE, and SK-65. .alpha.-d-Propoxyphene is probably comparable to codeine as an analgesic and is widely prescribed in combination with aspirin for the treatment of mild to moderate pain that is not adequately relieved by aspirin alone. Combinations of d-propoxyphene and aspirin (like those of codeine and aspirin) are more effective than either agent alone.
Preparation of d-propoxyphene was first described by A. Pohland and H. R. Sullivan at J. Am. Chem. Soc., Volume 75, pp. 4458(1953). Therein, the authors disclosed a synthesis involving several stages, (1) preparation of an aminoketone called .beta.-dimethylaminobutrophenone by addition of the secondary amine to phenylpropenyl ketone; (2) a Grignard reaction of the amino ketone with benzylmagnesium chloride to yield the amino, hydrochloride-carbinols described as .alpha.-(75%) and .beta.-(15%) 4-Dimethylamino-1,2-diphenyl-3-methyl-2-butanol Hydrochloride; and (3) acylation of the .alpha.-amino carbinol hydrochloride by addition of an equal weight of propionic anhydride and five times that weight of pyridine and heating to reflux for several hours. Note the following reaction formula: ##STR1##
After cooling to recover the crude product, it was purified by two recrystallizations from methanol-ethyl acetate solution resulting in a yield of 70%.
Although this work confirmed that the .alpha. and not the .beta.-diastereoisomers of propoxyphene gave rise to analgesic activity, it was still necessary to determine which of the optical forms of the .alpha.-diastereoisomer, i.e. .alpha.-d(+) or .alpha.-l(-) was responsible for the analgesic activity. Accordingly, Pohland and Sullivan reported in the J. Am. Chem. Soc., Volume 77, pp. 3400 (1955) their work on resolution of .alpha.-dl-4-Dimethylamino-1,2-diphenyl-3-methyl-2-butanol by fractional crystallization of its d-camphorsulfonic acid salt. From the respective .alpha.-d and .alpha.-l carbinol d-camphorsulfonic salts the optically active hydrochloride salts were prepared. The .alpha.-d-hydrochloride was acylated using propionic anhydride and triethylamine, while the .alpha.-l hydrochloride was acylated using propionic anhydride and pyridine. It was therein found that only the .alpha.-d stereoisomer gave the analgesic response. However, final purification of the hydrochloride salt required additional HCl and three recrystallizations and yields of less than about 70%.
In 1963, Pohland, Peters and Sullivan reported in the J. Org. Chem., Vol. 28, pp. 2483, an alternative synthetic route for .alpha.-d-propoxyphene hydrochloride. Working backwards from the desired optically active isomer of propoxyphene by its hydrolysis and dehydration to stilbene, followed by ozonization of the stilbene, the authors discovered good yield of (-)-.beta.-dimethylamino-.alpha.-methylpropiophenone. This optically active amino ketone was found to be surprisingly stable in salt from thus permitting its use as a starting material for a stereo selective synthesis of .alpha.-d-propoxyphene. Racemic .beta.-Dimethylamino-.alpha.-methylpropiophenone was resolved by crystallization of the dibenzoyl tartrate salts from acetone solution. The use of dibenzoyl-(-)-tartaric acid yielded the insoluble salt having (-)-.beta.-dimethylamino-.alpha.-methylpropiophenone, while the use of the (+) tartaric acid yielded the salt having the (+)-amino ketone isomer.
It is of interest that according to this reported synthesis, it was the (-) isomer of .beta.-dimethylamino-.alpha.-methylpropiophenone, which when liberatd from its (-) tartrate salt by Grignard reaction with benzylmagnesium chloride provided good yields of the (+) or (d) isomer of .alpha.-1,2-diphenyl-3-methyl-4-dimethylamino-2-butanol which of course is the carbinol precursor for .alpha.-d-propoxyphene. The reported yields were 69%. The acylation was accomplished as had been previously reported, i.e., by means of propionic anhydride in either triethylamine or pyridine.
More recently, in May of 1978, Hungarian Pat. No. 14,441 issued disclosing a synthesis of .alpha.-d-propoxyphene employing the above-described method except that (1) the (+)tartaric acid was employed in the resolution of the racemic .beta.-dimethylamino-.alpha.-methylpropiophenone and (2) the acylation was accomplished by reacting triethylamine in chloroform, propionyl chloride and the carbinol rather than propionyl anhydride and the carbinol hydrochloride. Still the product was precipitated in ether and required an amine catalyst.
Nevertheless, the reported yields of .alpha.-d-propoxyphene by the prior art anhydride esterifications are improved upon by the present invention.